A Fabry Disease Gene Therapy Study (MARVEL1)

A Phase 1/2, Baseline-controlled, Non-randomized, Open-label, Single-ascending Dose Study of a Novel Adeno-associated Viral Vector (FLT190) in Patients With Fabry Disease

This is a multinational, open-label study to assess the safety and efficacy of FLT190 in up to 15 adult male participants with classical Fabry disease.

Study Overview

• Status: Terminated
• Conditions: Lysosomal Storage Diseases; Fabry Disease
• Intervention / Treatment: Genetic: FLT190

Detailed Description

Patients who provide consent to participate in this study will be screened for eligibility.

Eligible patients will attend the study site on the day prior to infusion (Day -1) for a baseline visit. On Day 0, FLT190 will be administered as a single dose, slow intravenous infusion. Following FLT190 treatment the patient will be discharged from the investigational site and will continue to be monitored at outpatient visits for a period of approximately 9 months; following which, the patient will enter a period of long-term follow-up conducted under a separate protocol.

The study will be conducted in 2 parts;

Part 1: Enrolment of previously treated patients (Dose escalation)

Part 2: Enrolment of previously untreated patients (Dose expansion).

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Operations; Phone Number: +44 1438 906870; Email: contact@freeline.life

Study Locations

• Austria
  • Vienna, Austria
    • Medical University of Vienna
• Canada
  • Toronto
    • Calgary, Toronto, Canada, T2E 7Z4
      • Metabolics and Genetics in Calgary (MAGIC Clinic)
• Germany
  • Berlin, Germany
    • Charité - Universitätsmedizin Berlin
  • Hamburg, Germany
    • UKEA University Hospital Hamburg
  • Würzburg, Germany
    • University of Würzburg
• Italy
  • Napoli, Italy
    • Universita Federico II di Napoli
• Norway
  • Bergen, Norway
    • Haukeland University Hospital
• United Kingdom
  • London, United Kingdom
    • Royal Free Hospital
  • Salford, United Kingdom
    • Salford Royal NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • UPMC Children's Hospital of Pittsburgh
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Lysosomal and Rare Disorders Research and Treatment Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult males, ≥ 18 years of age with classic Fabry disease.
2. Confirmed diagnosis of classic Fabry Disease
3. Decreased plasma alpha galactosidase (αGLA) activity at screening.
4. One or more of the characteristic features of classic Fabry disease.
5. Estimated glomerular filtration rate (eGFR) ≥60mL/min/1.73m2 at screening.
6. <500 mg/g Urine Protein to Creatinine Ratio (UPCR) in a spot urine sample OR < 1g/24 hours of urinary protein (24hour urine analysis), at
7. Able to give full informed consent and able to comply with all requirements of the trial including the 5-year long term follow-up.
8. Willingness to practice barrier contraception whilst vector shedding via semen is present.
9. Lack of AAV neutralizing antibodies within 6 weeks prior to dosing.
10. For inclusion in Part 1, subjects must have received either a licensed ERT or PCT for at least 12 months prior to dosing. For inclusion in Part 2, subjects must never have been previously dosed with Enzyme Replacement Therapy (ER) or Pharmacological Chaperone Therapy (PCT).
11. Willingness to avoid strenuous exercise during first 3 months after dosing.

Exclusion Criteria:

1. Non-classical Fabry disease.
2. Prior hypersensitivity or intolerance to ERT
3. Prior lack of response to ERT.
4. Subjects with a history of chronic kidney disease for a minimum of 3 months.
5. Subjects with severe myocardial fibrosis.
6. Use of investigational therapy for Fabry disease within 60 days before enrolment. In addition, participation in any other clinical trial of an investigational medicinal product (IMP), and/or receiving any other IMP during the course of the study
7. Evidence of liver dysfunction as demonstrated by elevated blood levels during screening.
8. Platelet count < 100 xE9L.
9. Subjects receiving warfarin or other anticoagulants or subjects with a clinically significant bleeding disorder.

10 - 12. Either history of, or a positive serology test at screening for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), hepatitis C antibody (HCAb) and human immunodeficiency virus (HIV) or a negative test at screening for anti-varicella zoster virus (VZV) IgG or hepatitis surface antibody (HBsAb).

13. Subjects with a history of or a positive screening test for tuberculosis. 14. Subjects who have received a live attenuated vaccination within 12 weeks prior to screening or intend to receive such a vaccine within the course of the study.

15. Uncontrolled glaucoma, diabetes mellitus, or hypertension. 16. History of any malignancy requiring treatment. 17. History or detection of significant arrhythmia during screening. 18. Subjects with uncontrolled cardiac failure, unstable chest pain, or heart attack deemed significant in the past 6 months.

19. History of acute myocarditis or presence of acute myocarditis during screening.

20. Prior treatment with any gene therapy medicinal product. 21. Known or suspected intolerance to gadolinium, tacrolimus and other macrolides, steroids, local anesthetics used for skin or renal biopsies, or any non-investigational medicinal products (NIMPs) or their excipients.

22. Subjects with contraindications to MRI. Including subjects with ferromagnetic metallic implants, including pacing and defibrillator devices, nerve stimulators and cochlear implants.

23. Subjects who have had a renal transplant. 24. Cytomegalovirus immunoglobulin positive subjects who are CMV polymerase chain reaction (PCR) positive at screening.

25-26.History of physical or psychiatric illness that could affect the subject's ability to participate or a history of substance abuse including alcohol abuse.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FLT190; FLT190 is a recombinant adeno- associated viral (AAV) vector. Administered by a single intravenous infusion.	Genetic: FLT190; Gene Therapy product.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of treatment-emergent adverse events (AEs)	To investigate the safety of systemic administration of FLT190.	From screening to 12 weeks post infusion

Collaborators and Investigators

• Sponsor: Freeline Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2019
• Primary Completion (Actual): May 2, 2023
• Study Completion (Actual): May 2, 2023

Study Registration Dates

• First Submitted: July 26, 2019
• First Submitted That Met QC Criteria: July 30, 2019
• First Posted (Actual): July 31, 2019

Study Record Updates

• Last Update Posted (Actual): June 5, 2023
• Last Update Submitted That Met QC Criteria: June 2, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Gene Therapy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease; Lysosomal Storage Diseases
• Other Study ID Numbers: FLT190-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No